The pathogenesis of ACS centers on vulnerable atherosclerotic plaque disruption and subsequent thrombosis. Vulnerable plaques are characterized by a thin fibrous cap (under 65 micrometers), large lipid-rich necrotic core occupying over 40% of plaque area, abundant activated macrophages and T lymphocytes at the shoulder regions, reduced vascular smooth muscle cells (which produce stabilizing collagen), and neovascularization from the vasa vasorum (which promotes intraplaque hemorrhage). Matrix metalloproteinases (MMP-1, MMP-2, MMP-9) secreted by activated macrophages degrade collagen and elastin in the fibrous cap, weakening it until hemodynamic shear stress causes rupture. Upon rupture, exposed tissue factor binds factor VIIa to initiate the extrinsic coagulation pathway; simultaneously, collagen and von Willebrand factor recruit platelets. The P2Y12 receptor on platelets is the target of clopidogrel (irreversible, prodrug requiring CYP2C19 activation), prasugrel (irreversible, more predictable activation), and ticagrelor (reversible, direct-acting). The GP IIb/IIIa receptor targeted by abciximab, eptifibatide, and tirofiban represents the final common pathway of platelet aggregation. Thrombin generation is inhibited by unfractionated heparin and enoxaparin (AT-III dependent), bivalirudin (direct thrombin inhibitor), and fondaparinux (selective factor Xa inhibitor). The clinician must understand pharmacogenomics: CYP2C19...